Cholecystokinin-2 receptors (also referred to as cholecystokinin-2 receptor, CCK2R, CCKBR or CCK2) are regulatory peptides of the brain and gastrointestinal tract. CCK2R has been demonstrated to be overexpressed in certain human cancers. For example, CCK2R splice variants have been observed in human gastrointestinal and lung tumors. (See Korner, M. et al., J. Cell Mol. Med., 14, 4, 933-43 (2010)). Natural substrates of high affinity for cholecystokinin receptors include peptide hormones CCK and gastrin. C-terminal CCK peptide amide is selectively targeting CCK2R with 2 times higher affinity than binding to CCK1R. CCK2R has also been implicated in leukemia through immunoblotting of several leukemia cells lines. (See Stubbs, M. et al., Oncol. Rep., 14, 4, 1055-8 (2005).
The targeted delivery of drugs has been of recent interest, especially in the area of cancer therapy. Among the most well studied drug conjugates are anti-body drug conjugates (also known as ADCs) that have been designed as targeted therapies for cancer. (See Ducry, L. et al., Bioconjugate Chemistry, 21, 1, 5-13 (2010)). Examples of approved ADC treatments for cancer include Adcetris®, and Kadcyla®. Another promising avenue for the targeted delivery of drugs that has gained significant interest is the delivery of drug conjugates to a target cell through the binding of a receptor with a ligand. One example of such an approach is the delivery of a drug conjugate to a vitamin receptor through a vitamin receptor binding ligand. See for example, drug conjugates of folate described in U.S. Pat. No. 7,601,332.
The development of novel drug conjugates for delivery of therapeutic agents to molecular targets associated with cancer cells continues to be of great interest. Here we report the design and synthesis of novel CCK2-receptor drug conjugates.